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Discovery and Development of Seliciclib. How Systems Biology Journal of Biotechnology 202 (2015) 40–49 Contents lists available at ScienceDirect Journal of Biotechnology j ournal homepage: www.elsevier.com/locate/jbiotec Discovery and development of Seliciclib. How systems biology approaches can lead to better drug performance a b c a a,∗ Hilal S. Khalil , Vanio Mitev , Tatyana Vlaykova , Laura Cavicchi , Nikolai Zhelev a CMCBR, SIMBIOS, School of Science, Engineering and Technology, Abertay University, Dundee DD1 1HG, Scotland, UK b Department of Chemistry and Biochemistry, Medical University of Sofia, 1431 Sofia, Bulgaria c Department of Chemistry and Biochemistry, Medical Faculty, Trakia University, Stara Zagora, Bulgaria a r t i c l e i n f o a b s t r a c t Article history: Seliciclib (R-Roscovitine) was identified as an inhibitor of CDKs and has undergone drug development and Received 10 August 2014 clinical testing as an anticancer agent. In this review, the authors describe the discovery of Seliciclib and Received in revised form 26 February 2015 give a brief summary of the biology of the CDKs Seliciclib inhibits. An overview of the published in vitro Accepted 27 February 2015 and in vivo work supporting the development as an anti-cancer agent, from in vitro experiments to animal Available online 6 March 2015 model studies ending with a summary of the clinical trial results and trials underway is presented. In addition some potential non-oncology applications are explored and the potential mode of action of Keywords: Seliciclib in these areas is described. Finally the authors argue that optimisation of the therapeutic effects Seliciclib of kinase inhibitors such as Seliciclib could be enhanced using a systems biology approach involving Systems biology CDK mathematical modelling of the molecular pathways regulating cell growth and division. Crown Copyright © 2015 Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). 1. Introduction complex with its partner Cyclin B (CDK1/cyclin B), was required for prophase to metaphase transition, suggested that inhibitors of The cell cycle is a fundamental biological process that is tightly this kinase could be useful in the treatment of proliferative disor- regulated by the activity of a series of kinases termed the Cyclin- ders (Pondaven et al., 1990; Rialet and Meijer, 1991). Supporting Dependent Kinases (CDKs). These are such named because of the this hypothesis, Dimethylaminopurine (DMAP), a drug that was requirement for binding CDK specific cyclins for their activity initially identified as a potent inhibitor of mitosis in sea urchins (Grana˜ and Reddy, 1995). The activities of these kinases must fol- (Rebhun et al., 1973) was subsequently shown to exert its action low a specific sequence to allow normal cell cycle progression through inhibition of CDK1/cyclin B complex (Rialet and Meijer, (Morgan, 1997) and abberations in the control of the cell cycle 1991; Neant and Guerrier, 1988). DMAP and a related purine ␮ ␮ have been linked to a variety of diseases including cancer, inflam- isopentyladenine had in vitro IC50 values of 120 M and 55 M matory conditions and neurodegenerative disorders (Zhivotovsky against CDK1/cyclin B respectively. The fact that isopentyadenine and Orrenius, 2010). The cell cycle proceeds through various check- was an intermediate in the biosynthesis of the cytokinin group points each of which is regulated by the activity of CDKs that are in of plant hormones led to a collaboration between Laurent Mei- turn, regulated by signalling pathways either promoting or inhibit- jer of the Biological Station in Roscoff and Jaroslav Vesely and ing cell (Chiarle et al., 2001). Miroslav Strnad at the Institute of Experimental Botany in Olo- The first CDK to be discovered was CDK1, which was originally mouc in the Czech Republic. Their collaborative work resulted identified in starfish oocytes as “Maturation Promoting Factor” in the synthesis of a number of substituted purine molecules, or MPF. It was found that when oocytes previously arrested in the most promising of which was 2-(2-hydroxyethylamino)-6- the prophase of the cell cycle, were injected with CDK1, this benzylamino-9-methylpurine. This molecule, which was named caused their entry into metaphase, a process known to be asso- Olomoucine, was specific in its inhibitory action towards CDK and ciated with protein phosphorylation (Meijer and Guerrier, 1984; MAPK (Vesely´ et al., 1994), an observation which, at the time, Labbé et al., 1989). This observation, that the activity of CDK1, in was surprising for an ATP analogue. Olomoucine was consider- ably more potent with an IC50 value of 7 ␮M against CDK1/cyclin B in vitro. Strnad in collaboration with Michel Legraverend of ∗ the Institute Marie Curie at Orsay worked together to synthesise Corresponding author. Tel.: +44 1382308536. E-mail address: [email protected] (N. Zhelev). more potent and more specific substituted purines, the best of http://dx.doi.org/10.1016/j.jbiotec.2015.02.032 0168-1656/Crown Copyright © 2015 Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). H.S. Khalil et al. / Journal of Biotechnology 202 (2015) 40–49 41 Table 1 these kinases is required for initiation and progression of cellular Studies demonstrating CDK inhibition by Roscovitine in vitro and in vivo. division chemical inhibition of the CDKs has the potential to be CDK/Cyclin type Studied model Reference useful in proliferative diseases such as cancer. CDK1 Lung cancer cell line Schutte et al. (1997) CDK1 Human Colorectal cancer Abal et al. (2004) 2. CDK1 cell line CDK1/Cyclin B Xenopus oocytes Meijer et al. (1997) CDK1, also referred to as the mitotic kinase, forms a complex CDK1/Cyclin B In vitro kinase assay Meijer et al. (1997), Raynaud et al. (2005) with cyclin B (Malumbres and Barbacid, 2007) At 297 amino acids CDK1/Cyclin B In vitro kinase assay Meijer et al. (1997), in length and with a molecular weight of 34 kDa its activity is Raynaud et al. (2005) modulated by post-translational modification, being activated or CDK1, CDK2 Human Gastric cell lines Iseki et al. (1997) inhibited by site-specific phosphorylation by regulatory kinases CDK2 Human Pancreatic cell line Iseki et al. (1998) CDK2 Human Osteosarcoma, Zhang et al. (2004a,b) including Wee1, Mik1 amd Myt1 on Threonine 161,Tyrosine 15 or Cervical, Lung carcinoma Threonine 14 (Schafer, 1998). Hyperactivity of CDK1 either through cell lines overexpression of Cyclin B1 or hyperphosphoryation of CDK1 has CDK2/Cyclin A, E In vitro kinase assay Meijer et al. (1997), been observed, observed in several tumours, including breast-, & B Havlícek et al. (1997), colon- and prostate carcinoma (Pérez de Castro et al., 2007) this Biglione et al. (2007), Raynaud et al. (2005) supporting the hypothesis that dysregulation of this kinases could CDK2/Cyclin B Mouse lymphocytic Meijer et al. (1997) cause uncontrolled cellular division. leukaemia cell line CDK2, Cyclin E In vitro kinase assay, McClue et al. (2002) human tumour cell lines, 3. CDK2 mouse model CDK2/Cyclin B HCT116 colon cancer cell Raynaud et al. (2005) Dysregulation of CDK2 activity has also been observed in a vari- line ety of malignancies further supporting the theory that inhibition CDK2/Cyclin D1, Human breast cancer cell Nair et al. (2011) Cyclin A2 lines of the CDKs be Roscovitine could be beneficial in the treatment CDK4/Cyclin D1 In vitro kinase assay Meijer et al. (1997), of proliferative diseases. Although CDK2 is a key cell cycle regula- Raynaud et al. (2005) tor, critical for the transition into the S-phase of the cell cycle, mice CDK4/Cyclin D1 HCT116 colon cancer cell Raynaud et al. (2005) lacking the kinase are viable, suggesting that there are other kinases line which can compensate for any lack in CDK2 activity (Berthet et al., CDK5/P35 In vitro kinase assay Meijer et al. (1997) CDK6/Cyclin D3 In vitro kinase assay Meijer et al. (1997), 2003). CDK2 activity is controlled not just by phosphorylation Raynaud et al. (2005) events by complexation with inhibitory protein partners such as CDK7/Cyclin H Invitro kinase assay Raynaud et al. (2005) Cip/Kip and of course its cyclin partners Cyclin E and Cyclin A dys- CDK9/Cyclin T1 In vitro kinase assay & Hela Biglione et al. (2007), regulation of which has been observed in malignancies (Pérez de cells Raynaud et al. (2005) Castro et al., 2007). which, 6-(benzylamino)-2(R)-[[1-(hydroxymethyl)propyl]amino]- 4. CDK5 9-isopropylpurine, termed Roscovitine, had an in vitro IC50 value of ␮ 0.45 M against the CDK1/cylin B complex (Havlícek et al., 1997). CDK5 is required for central and peripheral nervous system Roscovitine and olomoucine were subsequently co-crystallised function (Cruz and Tsai, 2004) and has been implicated in numer- with CDK2 and these structures were used as the basis of molecular ous neuronal functions including cytoarchitecture in the brain, models for guiding further medicinal chemistry programmes (De neuronal migration, synaptic plasticity, learning and memory and Azevedo et al., 1997). may be involved in the development of neurodegenerative disor- Roscovitine has been demonstrated to be a potent inhibitor of a ders including Alzheimer’s and Parkinson’s Diseases (Angelo et al., ␮ number of CDKs including CDK1/cyclin B (0.65 M), CDK2/cyclin A 2006; Cruz and Tsai, 2004; Dhavan and Tsai, 2001). Treatment of ␮ ␮ ␮ (0.7 M), CDK2/cyclin E (0.7 M), CDK5/p35 (0.2 M), CDK7/cyclin the lower eukaryote Dictyostelium discoideum with Roscovitine ␮ ␮ H (0.49 M), and CDK9/cyclin H (0.79 M). However, because led to an inhibition not only of the single-cell growth phase of the Roscovitine is an ATP competitive molecule, the precise IC50 values organism but also arrested translocation of the protein between reported vary depending on the concentration of ATP used in the the nucleus and cytoplasm raising the possibility that at least part in vitro assay (Wang and Fischer, 2008; Meijer et al., 1997; McClue of the biological effects of Roscovitine may be due to secondary et al., 2002; Biglione et al., 2007).
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